Dysregulated skin barrier function in Tmem79 mutant mice promotes IL-17A-dependent spontaneous skin and lung inflammation.

BACKGROUND: Atopic dermatitis (AD) is associated with a dysregulation of the skin barrier and may predispose to the development of secondary allergic conditions, such as asthma. Tmem79ma/ma mice harbor a mutation in the gene encoding Transmembrane Protein 79 (or Mattrin), which has previously been associated with AD. As a result of the Tmem79 gene mutation, these mice have a defective skin barrier and develop spontaneous skin inflammation. In this study, Tmem79ma/ma mice were assessed for the underlying immunological response in the development of spontaneous skin and lung inflammation. METHODS: Development of spontaneous skin and lung inflammation in Tmem79ma/ma mice was analyzed. We further investigated susceptibility to cutaneous Staphylococcus aureus infection. Tmem79ma/ma were crossed to IL-17A-deficient mice to address the contribution of IL-17A to spontaneous skin and lung disease. RESULTS: Tmem79ma/ma mice developed IL-17A-dependent spontaneous AD-like inflammation and were refractory to S aureus infection. Mutant mice progressed to airway inflammation subsequent to the occurrence of dermatitis. The progression from skin to lung disease is dependent on adaptive immunity and is facilitated by cutaneous expansion of Th17 and TCRγδ T cells. CONCLUSION: Mice lacking Tmem79/Mattrin expression have a defective skin barrier. In adulthood, these mice develop dermatitis with secondary progression to lung inflammation. The development of skin and lung inflammation is IL-17A-dependent and mediated by TCRγδ T cells.

Lichen planus affecting the female genitalia: A retrospective review of patients at Mayo Clinic.

BACKGROUND: Genital or vulval lichen planus (VLP) may have a disabling effect on a patient's quality of life. Evidence-based management guidelines are lacking for VLP. OBJECTIVE: We sought to review clinical presentation and treatment of patients who received a diagnosis of VLP. METHODS: The 100 consecutive patients who received a diagnosis of VLP at Mayo Clinic between January 1, 1997, and December 31, 2015, were reviewed retrospectively. Descriptive statistics were used for data analysis. Fisher's exact test and the Wilcoxon rank sum test were used for analysis of categorical and continuous variables, respectively. All statistical tests were 2 sided, with the α level set at .05 for statistical significance. RESULTS: The time to diagnosis for 49% of patients was more than 1 year. Three patients (3%) had vulval dysplasia, including invasive squamous cell carcinoma. Sixty-eight patients (68%) had multisite lichen planus disease. Eleven patients (11%) had disease remission. Dermatology was the lead specialty for 9 of these cases of remission. LIMITATIONS: This was a retrospective, small-cohort study. CONCLUSION: A low frequency of disease remission was seen in patients with VLP. Patients with lichen planus benefit considerably from dermatology consultation. Further research is warranted to establish high-quality, evidence-based guidelines for multidisciplinary management of this challenging disease.

Final Diagnosis of 112 Girls Presenting With Genital Mucocutaneous Symptoms and Signs: The Mayo Clinic Experience.

Pediatric genital mucocutaneous diseases are rare. A retrospective review was performed of children presenting with symptomatology of genital dermatoses to a hospital-based dermatology service. This study highlights that the range of genital diseases in children is not as broad as in adults. The diagnosis of genital mucocutaneous disease in children is usually genital lichen sclerosus, but other diagnoses should be considered.

A genome-wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis.

Atopic dermatitis (AD) is the most common dermatological disease of childhood. Many children with AD have asthma and AD shares regions of genetic linkage with psoriasis, another chronic inflammatory skin disease. We present here a genome-wide association study (GWAS) of childhood-onset AD in 1563 European cases with known asthma status and 4054 European controls. Using Illumina genotyping followed by imputation, we generated 268 034 consensus genotypes and in excess of 2 million single nucleotide polymorphisms (SNPs) for analysis. Association signals were assessed for replication in a second panel of 2286 European cases and 3160 European controls. Four loci achieved genome-wide significance for AD and replicated consistently across all cohorts. These included the epidermal differentiation complex (EDC) on chromosome 1, the genomic region proximal to LRRC32 on chromosome 11, the RAD50/IL13 locus on chromosome 5 and the major histocompatibility complex (MHC) on chromosome 6; reflecting action of classical HLA alleles. We observed variation in the contribution towards co-morbid asthma for these regions of association. We further explored the genetic relationship between AD, asthma and psoriasis by examining previously identified susceptibility SNPs for these diseases. We found considerable overlap between AD and psoriasis together with variable coincidence between allergic rhinitis (AR) and asthma. Our results indicate that the pathogenesis of AD incorporates immune and epidermal barrier defects with combinations of specific and overlapping effects at individual loci.

High-density genotyping study identifies four new susceptibility loci for atopic dermatitis.

Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds, and recent data indicate a role for autoreactivity in at least a subgroup of patients. FLG (encoding filaggrin) has been identified as a major locus causing skin barrier deficiency. To better define risk variants and identify additional susceptibility loci, we densely genotyped 2,425 German individuals with atopic dermatitis (cases) and 5,449 controls using the Immunochip array followed by replication in 7,196 cases and 15,480 controls from Germany, Ireland, Japan and China. We identified four new susceptibility loci for atopic dermatitis and replicated previous associations. This brings the number of atopic dermatitis risk loci reported in individuals of European ancestry to 11. We estimate that these susceptibility loci together account for 14.4% of the heritability for atopic dermatitis.